CD4(-ALPHA IN RESPONSE TO IN-VITRO HIV-1 INFECTION() BLOOD DENDRITIC CELLS AVE POTENT PRODUCERS OF IFN)

We determined the relative abilities of cell subpopulations from all m ajor PBMC lineages of normal donors to produce IFN-alpha in response t o in vitro stimulation with lymphocytotropic H1V-1 (IIIb and RF), mono cytotropic HIV-1 (BaL), Sendai virus, and HSV-1 Active and inactive ce ll-free preparations of HIV-1 IIIb and cell-associated HIV-1 IIIb, and active cellfree preparations of the other viruses, induced comparable , maximal levels of acid-stable IFN-alpha in PBMC by 18 to 24 h. Negat ive selection and enrichment experiments indicated that HLA-DR(+) ''nu ll'' cells produced the majority of the IFN-alpha. A positive selectio n protocol using flow cytometric sorting enriched these HLA-DR(+) CD3( -) CD19(-) CD16(-) CD56(-) CD14(-) cells to >95% purity. These were id entified as dendritic cells by their phenotype, large size, and veiled and ruffled morphology. The purified dendritic cells produced as much as 60-fold more IFN-alpha compared with purified, HLA-DR(+) CD14(+) m onocytes in response to the viruses. IFN-alpha was not produced by CD3 (+) T cells or CD56(+) NK cells. Purified CD19(+) B cells produced a m inimal amount of IFN-alpha in response to Sendai virus, and no IFN-alp ha in response to the other viruses. Of significance, the dendritic ce lls expressed CD4 at a density similar to monocytes, and induction of IFN-alpha by HIV-1 could be blocked by HIV-1 gp120 anti-serum or anti- CD4 mAb. We conclude that the production of IFN-alpha constitutes a pr eviously unrecognized major function of blood dendritic cells. This ma y be a mechanism of innate immunity mediated by dendritic cells agains t HIV-1 and other viral infections.